The long-term goal of the project is to understand the mechanisms underlying the adverse effect of chronic hypoxia on uterine blood flow in pregnancy. Chronic hypoxia during the course of pregnancy is one of the most common insults to the maternal cardiovascular system and fetal development, and is associated with an increased risk of preeclampsia and fetal intrauterine growth restriction. Previous studies have demonstrated that hypoxia has profound effects on uterine vascular reactivity and inhibits pregnancy induced adaptation of uterine artery contractility. Although molecular mechanisms remain poorly understood, recent studies have suggested genomic mechanisms of the steroid hormones, estrogen and progesterone in regulating pressure-dependent myogenic tone of the uterine artery in adaptation to pregnancy. Pressure-dependent myogenic contraction is an important physiological mechanism that regulates basal vascular tone and contributes significantly to the modulation of organ blood flow. The preliminary studies demonstrated that long-term high altitude hypoxia during pregnancy significantly increased the myogenic reactivity in the uterine artery of pregnant sheep and eliminated the differences in pressure-induced myogenic tone in uterine arteries between nonpregnant and pregnant animals. The proposed studies will focus on the mechanisms and test the main hypothesis that chronic hypoxia inhibits the steroid hormones (estrogen and progesterone)-mediated adaptation of ERK1/2 and PKC signaling pathways, resulting in increased myogenic tone of the uterine artery in pregnancy. To test this hypothesis, three Specific Aims are proposed to determine whether and to what extent long-term high altitude hypoxia during pregnancy 1) inhibits steroids-mediated upregulation of ERK1/2 gene expression and downregulation of the PKC activity in the uterine artery, 2) inhibits steroids-mediated down regulation of pressure-dependent myogenic tone in the uterine artery, and 3) whether chronic hypoxia has direct effects on the steroids-mediated responses in the uterine arteries. The results will provide exciting novel insights in biochemical, molecular, cellular, and pathophysiological adaptation mechanisms involved in altering uteroplacental circulation in response to hypoxia in pregnancy, which has obvious clinical significance because the maladaptation of uterine circulation caused by chronic hypoxia in pregnancy is associated with fetal developmental abnormalities and maternal cardiovascular disorders.